title: Cardiopulmonary arrest and resuscitation disrupts cholinergic anti-inflammatory processes: a role for cholinergic α7 nicotinic receptors.
abstract: Cardiac arrest is a leading cause of death worldwide. While survival rates following sudden cardiac arrest remain relatively low, recent advancements in patient care have begun to increase the proportion of individuals who survive cardiac arrest. However, many of these individuals subsequently develop physiological and psychiatric conditions that likely result from ongoing neuroinflammation and neuronal death. The present study was conducted to better understand the pathophysiological effects of cardiac arrest on neuronal cell death and inflammation, and their modulation by the cholinergic system. Using a well validated model of cardiac arrest, here we show that global cerebral ischemia increases microglial activation, proinflammatory cytokine mRNA expression (interleukin-1β, interleukin-6, tumor necrosis factor-α), and neuronal damage. Cardiac arrest also induces alterations in numerous cellular components of central cholinergic signaling, including a reduction in choline acetyltransferase enzymatic activity and the number of choline acetyltransferase-positive neurons, as well as, reduced acetylcholinesterase and vesicular acetylcholine transporter mRNA. However, treatment with a selective agonist of the α7 nicotinic acetylcholine receptor, the primary receptor mediating the cholinergic anti-inflammatory pathway, significantly decreases the neuroinflammation and neuronal damage resulting from cardiac arrest. These data suggest that global cerebral ischemia results in significant declines in central cholinergic signaling, which may in turn diminish the capacity of the cholinergic anti-inflammatory pathway to control inflammation. Furthermore, we provide evidence that pharmacological activation of α7 nicotinic acetylcholine receptors provide significant protection against ischemia-related cell death and inflammation within a clinically relevant time frame.
authors.affiliation: Department of Psychology, The Ohio State University, Columbus, Ohio 43210, USA. norman.106@osu.edu
authors.forename: Greg J
authors.initials: GJ
authors.lastname: Norman
authors.forename: John S
authors.initials: JS
authors.lastname: Morris
authors.forename: Kate
authors.initials: K
authors.lastname: Karelina
authors.forename: Zachary M
authors.initials: ZM
authors.lastname: Weil
authors.forename: Ning
authors.initials: N
authors.lastname: Zhang
authors.forename: Yousef
authors.initials: Y
authors.lastname: Al-Abed
authors.forename: Holly M
authors.initials: HM
authors.lastname: Brothers
authors.forename: Gary L
authors.initials: GL
authors.lastname: Wenk
authors.forename: Valentin A
authors.initials: VA
authors.lastname: Pavlov
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Tracey
authors.forename: A Courtney
authors.initials: AC
authors.lastname: Devries
mesh_terms: D000818:Animals; D001597:Benzylidene Compounds / Q000008:administration & dosage; D002545:Brain Ischemia / Q000188:drug therapy / Q000503:physiopathology*; D006323:Heart Arrest / Q000188:drug therapy / Q000473:pathology* / Q000503:physiopathology; D018836:Inflammation Mediators / Q000008:administration & dosage / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018722:Nicotinic Agonists / Q000008:administration & dosage; D011725:Pyridines / Q000008:administration & dosage; D011897:Random Allocation; D011978:Receptors, Nicotinic / Q000502:physiology*; D012151:Resuscitation / Q000009:adverse effects* / Q000379:methods; D015398:Signal Transduction / Q000502:physiology; D013997:Time Factors; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: D001597:Benzylidene Compounds; C579166:Chrna7 protein, mouse; D018836:Inflammation Mediators; D018722:Nicotinic Agonists; D011725:Pyridines; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; C088936:3-(2,4-dimethoxybenzylidene)anabaseine